High-intensity interval training attenuates the progression of diastolic and skeletal muscle dysfunction in the two-hit mouse model of HFpEF

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is a multifactorial syndrome characterized by diastolic dysfunction, metabolic disturbances, and skeletal muscle impairments. Exercise training has been recommended as non-pharmacological therapy for HFpEF. Yet its effects on cardiac, renal, skeletal muscle, and metabolic homeostasis remain incompletely understood. AIM We investigated the systemic effects of exercise training in the "two-hit" mouse model of HFpEF. METHODS Male C57BL/6 N mice were assigned to either a sedentary HFpEF group (20 weeks) (n = 10) or a high-intensity interval training (HIIT) intervention for five weeks (training was initiated in the 15th week of the protocol) (n = 10), and a control group (n = 8). Cardiac function was assessed via echocardiography, while glucose metabolism, renal function, and skeletal muscle adaptations were evaluated through metabolic assays, histological analyses, and molecular studies. RESULTS HIIT reduced diastolic dysfunction, as indicated by a slightly lower E/e' ratio and reduced myocardial collagen deposition. Skeletal muscle integrity was improved, with a higher proportion of oxidative fibers in the gastrocnemius, while the quadriceps showed hypertrophy in both oxidative and less oxidative fibers. It also promotes an anabolic environment and mitochondrial enhancement. Force generation was also increased. Furthermore, HIIT reduced insulin levels without affecting renal function but decreased markers of kidney damage. CONCLUSIONS These findings demonstrate that HIIT attenuates diastolic and skeletal muscle dysfunction in the two-hit HFpEF mice model. Understanding how exercise training influences HFpEF phenotypes could provide novel insights into therapeutic strategies for patients with cardiovascular and metabolic comorbidities.